Pimobendane: Difference between revisions

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| verifiedrevid = 408556559
| verifiedrevid = 408556559
| IUPAC_name = (''RS'')-6-[2-(4-methoxyphenyl)-1''H''-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2''H'')-one
| IUPAC_name = (''RS'')-6-[2-(4-methoxyphenyl)-1''H''-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2''H'')-one
| image = Pimobendan.png
| image = Pimobendan skeletal.png
| width = 200px
| width = 200px
| imagename = 1 : 1 mixture (racemate)
| imagename = 1 : 1 mixture (racemate)
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| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 24646
| ChEMBL = 24646
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID      = 4657


<!--Chemical data-->
<!--Chemical data-->
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| molecular_weight = 334.37 g/mol
| molecular_weight = 334.37 g/mol
| smiles = CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC
| smiles = CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC
| InChI            = 1/C19H18N4O2/c1-11-9-17(24)22-23-18(11)13-5-8-15-16(10-13)21-19(20-15)12-3-6-14(25-2)7-4-12/h3-8,10-11H,9H2,1-2H3,(H,20,21)(H,22,24)
| InChIKey          = GLBJJMFZWDBELO-UHFFFAOYAK
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI          = 1S/C19H18N4O2/c1-11-9-17(24)22-23-18(11)13-5-8-15-16(10-13)21-19(20-15)12-3-6-14(25-2)7-4-12/h3-8,10-11H,9H2,1-2H3,(H,20,21)(H,22,24)
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey      = GLBJJMFZWDBELO-UHFFFAOYSA-N
}}
}}
__NOTOC__
__NOTOC__
{{SI}}
{{SI}}
{{CMG}}
{{CMG}}


==Overview==
==Overview==
'''Pimobendan''' ([[International Nonproprietary Name|INN]] is a veterinary medication manufactured by [[Boehringer Ingelheim]] under the trade names '''Vetmedin''' and '''Acardi''') or '''pimobendane'''. It is a calcium sensitizer with positive [[inotropic]] and [[vasodilator]] effects. It is also a selective [[phosphodiesterase inhibitor|inhibitor]] of [[phosphodiesterase]] III ([[PDE3]]).
''Pimobendan''' (or '''pimobendane'')([[International Nonproprietary Name|INN]]) is a veterinary medication manufactured by [[Boehringer Ingelheim]] under the trade names '''Vetmedin''' and '''Acardi''' (Japan). It is both a calcium sensitizer and a selective inhibitor of [[phosphodiesterase]] III ([[PDE3]]) with positive [[inotropic]] and [[vasodilator]] effects.


Pimobendan is used in the management of [[heart failure]] in dogs, most commonly caused by myxomatous mitral valve disease (also known as [[endocardiosis]]), or [[dilated cardiomyopathy]].<ref>{{cite journal |author=Gordon SG, Miller MW, Saunders AB |title=Pimobendan in heart failure therapy—a silver bullet? |journal=J Am Anim Hosp Assoc |volume=42 |issue=2 |pages=90–3 |year=2006 |pmid=16527909 |doi= |url=http://www.jaaha.org/cgi/pmidlookup?view=long&pmid=16527909}}</ref> Research has shown that pimobendan increases survival time and improves quality of life in patients with [[congestive heart failure]] secondary to mitral valve disease when compared with [[benazepril]], an [[ACE inhibitor|angiotensin-converting-enzyme (ACE) inhibitor]].<ref>{{cite journal |author=Häggström J, Boswood A, O'Grady M, ''et al.'' |title=Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study |journal=J. Vet. Intern. Med. |volume= 22|issue= 5|pages= 1124|date=July 2008 |pmid=18638016 |doi=10.1111/j.1939-1676.2008.0150.x |url=}}</ref> Under the trade name Acardi, it is available for human use in [[Japan]].<ref>{{cite web |url=http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=54 |title=Kusuri-no-Shiori Drug Information Sheet |date=April 2005 |publisher=RAD-AR Council, Japan |accessdate=2008-08-06}}</ref>
Pimobendan is used in the management of [[heart failure]] in dogs, most commonly caused by myxomatous mitral valve disease (also previously known as endocardiosis), or [[dilated cardiomyopathy]].<ref>{{cite journal |author=Gordon SG, Miller MW, Saunders AB |title=Pimobendan in heart failure therapy—a silver bullet? |journal=J Am Anim Hosp Assoc |volume=42 |issue=2 |pages=90–3 |year=2006 |pmid=16527909 |doi= |url=http://www.jaaha.org/cgi/pmidlookup?view=long&pmid=16527909}}</ref> Research has shown that pimobendan increases survival time and improves quality of life in canine patients with [[congestive heart failure]] secondary to mitral valve disease when compared with [[benazepril]], an [[ACE inhibitor|angiotensin-converting-enzyme (ACE) inhibitor]].<ref>{{cite journal |author=Häggström J, Boswood A, O'Grady M, ''et al.'' |title=Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study |journal=J. Vet. Intern. Med. |volume= 22|issue= 5|pages= 1124–35|date=July 2008 |pmid=18638016 |doi=10.1111/j.1939-1676.2008.0150.x |url=}}</ref> Under the trade name Acardi, it is available for human use in [[Japan]].<ref>{{cite web |url=http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=54 |title=Kusuri-no-Shiori Drug Information Sheet |date=April 2005 |publisher=RAD-AR Council, Japan |accessdate=2008-08-06}}</ref>


==Mechanism of action==
==Mechanism of action==
Pimobendan is a positive [[inotrope]]. It sensitizes and increases the binding efficiency of cardiac [[myofibril]] to the calcium ions that are already present without increasing the consumption of oxygen and energy. Pimobendan also causes peripheral [[vasodilation]] by inhibiting the function of [[PDE3|phosphodiesterase III]]. This results in decreased pressure, translating into smaller cardiac [[preload (cardiology)|preload]] and [[afterload]] (decreases the failing heart's workload).
Pimobendan is a positive [[inotrope]] (increases myocardial contractility). It sensitizes and increases the binding efficiency of cardiac troponin in the [[myofibril]] to the calcium ions that are already present in systole. In normal hearts it increases the consumption of oxygen and energy to the same degree as dobutamine but in diseased hearts it may not.<ref>Hata K1, Goto Y, Futaki S, Ohgoshi Y, Yaku H, Kawaguchi O, Takasago T, Saeki A, Taylor TW, Nishioka T, et al. Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine. Circulation. 1992 Oct;86(4):1291-301.</ref> <ref>Goto Y1, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels. 1997;Suppl 12:103-5.</ref> Pimobendan also causes peripheral [[vasodilation]] by inhibiting the function of [[PDE3|phosphodiesterase III]]. This results in decreased resistance to blood flow through systemic arterioles, which decreases [[afterload]] (decreases the failing heart's workload) and reduces the amount of mitral regurgitation.<ref>Verdouw PD, Hartog JM, Duncker DJ, Roth W, Saxena PR. Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol. 1986 Jul 15;126(1-2):21-30.</ref><ref>Kanno N, Kuse H, Kawasaki M, Hara A, Kano R, Sasaki Y. Effects of pimobendan for mitral valve regurgitation in dogs. J Vet Med Sci. 2007 Apr;69(4):373-7.</ref>


==Pharmacokinetics==
==Pharmacokinetics==
Pimobendan is absorbed rapidly when given via the oral route and has a [[bioavailability]] of 60-65%. It is metabolized into its active form by the [[liver]]. The [[half-life]] of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% [[plasma protein binding|bound to plasma proteins]] in circulation. This has implications in patients suffering from low blood protein levels ([[hypoproteinemia]]/[[hypoalbuminemia]]) and with patients that are on concurrent therapies that are also highly protein bound.
Pimobendan is absorbed rapidly when given via the oral route and has a [[bioavailability]] of 60-65%.<ref>http://www.vetmedin.com/Vetmedin%20Insert_6-07.pdf</ref> Bioavailability is markedly decreased when ingested with food. It is metabolized into an active metabolite (desmethylpimobendan) by the [[liver]]. The parent compound, pimobendan, is a potent calcium sensitizer while desmethylpimobendan is a more potent phosphodiesterase III inhibitor.<ref>Hanzlicek AS1, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, Olson EE, Margiocco M. Pharmacokinetics of oral pimobendan in healthy cats. J Vet Cardiol. 2012 Dec;14(4):489-96.</ref> The [[half-life]] of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% [[plasma protein binding|bound to plasma proteins]] in circulation. This may have implications in patients suffering from low blood protein levels ([[hypoproteinemia]]/[[hypoalbuminemia]]) and in patients that are on concurrent therapies that are also highly protein bound.


==Combinations==
==Combinations==
Pimobendan is often used in combination with three other drugs to palliate dogs with heart disease and reduce clinical signs of disease. These are:
Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are:
* [[Furosemide]], a diuretic, to reduce [[pulmonary edema]].  This can be given intravenously if the animal is in respiratory distress (6–8&nbsp;mg/kg), and then titrated down to the minimum dose required orally.
* [[Furosemide]], a diuretic, to reduce [[edema]] and effusion.
* [[Spironolactone]], an [[aldosterone antagonist]]. This has two actions, firstly, as a [[potassium-sparing diuretic]], although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial remodelling and fibrosis, slowing the progression of heart disease.
* [[Spironolactone]], an [[aldosterone antagonist]]. This has two actions, firstly, as a [[potassium-sparing diuretic]], although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial fibrosis, possibly slowing the progression of heart disease.
*An [[ACE inhibitor]], often [[enalapril]] (trade name Enacard) or [[benazepril]] (Fortekor). These drugs inhibit the action of [[angiotensin-converting enzyme]], producing a balanced vasodilation, along with other favourable effects.
*An [[ACE inhibitor]], often [[enalapril]] (trade name Enacard) or [[benazepril]] (Fortekor). These drugs inhibit the action of [[angiotensin-converting enzyme]], producing a balanced vasodilation, along with other potentially favorable effects.


Other drugs may also be used as required to manage certain [[arrhythmias]] that are often associated with heart disease.
Other drugs may also be used as required to manage certain [[arrhythmias]] that are often associated with heart disease.


==Chemistry==
==Synthesis==
Pimobendan can be synthesized beginning with [[anisoyl chloride]]:<ref>{{cite journal|doi=10.1002/jlcr.2580230806|author=Nicolas, C; Verny, M; Maurizis, J. C.; Payard, M.; Faurie, M|title=Synthesis of14C-bucromarone succinate and hydrochloride |journal=J. Labeled Cmpd. Radiopharm. | year= 1986 |volume=23 | pages=837}}</ref>
Pimobendan can be synthesized beginning with [[anisoyl chloride]].
:[[File:PimobendanStructure.png|600px]]
[[File:Pimobendan.png|700px|center|thumb|Pimobendan synthesis:<ref>{{Cite doi|10.1002/jlcr.2580230806}}</ref>]]
 
==See also==
*[[Levosimendan]]


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


{{Phosphodiesterase inhibitors}}
{{Phosphodiesterase inhibitors}}
{{Cardiac stimulants excluding cardiac glycosides}}
{{Vasodilators used in cardiac diseases}}


[[Category:Phosphodiesterase inhibitors]]
[[Category:Benzimidazoles]]
[[Category:Cardiovascular Drugs]]
[[Category:Lactams]]
[[Category:PDE3 inhibitors]]
[[Category:Calcium sensitizers]]
[[Category:Inotropic agents]]
[[Category:Vasodilators]]
[[Category:Pyridazines]]
[[Category:Phenol ethers]]
[[Category:Drug]]
[[Category:Drug]]

Revision as of 21:04, 28 April 2015

Pimobendan
File:Pimobendan skeletal.png
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATCvet code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability60 to 65%
Elimination half-life0.4 hours
ExcretionIn feces
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC19H18N4O2
Molar mass334.37 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pimobendan (or pimobendane)(INN) is a veterinary medication manufactured by Boehringer Ingelheim under the trade names Vetmedin and Acardi (Japan). It is both a calcium sensitizer and a selective inhibitor of phosphodiesterase III (PDE3) with positive inotropic and vasodilator effects.

Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also previously known as endocardiosis), or dilated cardiomyopathy.[1] Research has shown that pimobendan increases survival time and improves quality of life in canine patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, an angiotensin-converting-enzyme (ACE) inhibitor.[2] Under the trade name Acardi, it is available for human use in Japan.[3]

Mechanism of action

Pimobendan is a positive inotrope (increases myocardial contractility). It sensitizes and increases the binding efficiency of cardiac troponin in the myofibril to the calcium ions that are already present in systole. In normal hearts it increases the consumption of oxygen and energy to the same degree as dobutamine but in diseased hearts it may not.[4] [5] Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase III. This results in decreased resistance to blood flow through systemic arterioles, which decreases afterload (decreases the failing heart's workload) and reduces the amount of mitral regurgitation.[6][7]

Pharmacokinetics

Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%.[8] Bioavailability is markedly decreased when ingested with food. It is metabolized into an active metabolite (desmethylpimobendan) by the liver. The parent compound, pimobendan, is a potent calcium sensitizer while desmethylpimobendan is a more potent phosphodiesterase III inhibitor.[9] The half-life of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This may have implications in patients suffering from low blood protein levels (hypoproteinemia/hypoalbuminemia) and in patients that are on concurrent therapies that are also highly protein bound.

Combinations

Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are:

Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease.

Synthesis

Pimobendan can be synthesized beginning with anisoyl chloride.

Pimobendan synthesis:[10]

See also

References

  1. ↑ Gordon SG, Miller MW, Saunders AB (2006). "Pimobendan in heart failure therapy—a silver bullet?". J Am Anim Hosp Assoc. 42 (2): 90–3. PMID 16527909.
  2. ↑ Häggström J, Boswood A, O'Grady M; et al. (July 2008). "Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study". J. Vet. Intern. Med. 22 (5): 1124–35. doi:10.1111/j.1939-1676.2008.0150.x. PMID 18638016.
  3. ↑ "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.
  4. ↑ Hata K1, Goto Y, Futaki S, Ohgoshi Y, Yaku H, Kawaguchi O, Takasago T, Saeki A, Taylor TW, Nishioka T, et al. Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine. Circulation. 1992 Oct;86(4):1291-301.
  5. ↑ Goto Y1, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels. 1997;Suppl 12:103-5.
  6. ↑ Verdouw PD, Hartog JM, Duncker DJ, Roth W, Saxena PR. Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol. 1986 Jul 15;126(1-2):21-30.
  7. ↑ Kanno N, Kuse H, Kawasaki M, Hara A, Kano R, Sasaki Y. Effects of pimobendan for mitral valve regurgitation in dogs. J Vet Med Sci. 2007 Apr;69(4):373-7.
  8. ↑ http://www.vetmedin.com/Vetmedin%20Insert_6-07.pdf
  9. ↑ Hanzlicek AS1, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, Olson EE, Margiocco M. Pharmacokinetics of oral pimobendan in healthy cats. J Vet Cardiol. 2012 Dec;14(4):489-96.
  10. ↑ Template:Cite doi


Template:Phosphodiesterase inhibitors

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